Polyzwitterions are employed as coating polymers for biomaterials to induce an antifouling property on the surface.F ine-tuning the betaine structure switches the antifouling property to be interactive with anionic tissue constituents in response to at umorous pH gradient. The ethylenediamine moiety in the carboxybetaine enabled stepwise protonation and initiated the di-protonation process around tumorous pH (6.5). The net charge of the developed polyzwitterion (PGlu(DET-Car)) was thus neutral at pH 7.4 for antifouling, but was cationic at pH 6.5 for interaction with anionic constituents.Q uantum dots coated with PGlu(DET-Car) exhibited comparable stealth and enhanced tumor accumulation relative to the PEG system. The present study provides an ovel design of smart switchable polyzwitterion based on aprecise control of the net charge.Thesurfaceofbiomaterialsdeterminestheir interaction with the surrounding biological substances.I np articular, nanomaterials for tumor-targeted therapy,l oading therapeutic molecules such as antitumor drugs and imaging agents, [1][2][3][4][5][6] have to avoid undesired interactions with blood components and normal tissues [7] until reaching the tumor sites; [8] the interactions are often associated with quick elimination from blood stream mostly based on the recognition by reticuloendothelial system (RES). [9] To this end, coating by biologically inert polymers,that is,antifouling (or stealth) polymers,such as poly(ethylene glycol) (PEG), endows foreign nanomaterials (for example,q uantum dots (QDs), dendrimers,p olymeric micelles,a nd liposomes) [1][2][3][4] with prolonged blood circulation [9] for effective tumor accumulation through the leaky tumor vasculature. [2] In this regard, polyzwitterions have garnered increasing attention as antifouling polymers. [10,11] Theb etaine structure has two ionizable groups with opposite charges,a nd polyzwitterions are allowed to exhibit antifouling property when the charge balance is neutral within the betaine structure. [12] Thea ntifouling performance of polyzwitterions depends on pH, owing to the ionizable groups in the betaine structure, [12] and thus neutral net charge of betaine structure at physiological pH 7.4 is necessary for coating of nanomaterials with polyzwitterion as as tealth polymer.I nt his regard, appropriate ionizable moieties in the betaine structure would install tailored pH-responsiveness into polyzwitterions for the design of am olecular program that switches the antifouling property likely to become interactive with biological substances below (or above) as pecific pH. To this end, extracellular pH in tumor tissues is acidic (ca. 6.5) relative to normal tissues (7.4), on the basis of Warburg effect, where activated anaerobic respiration and associated high rate of glycolysis lead to augmented production of acidic metabolites (for example,lactate). [13] Herein, we report that the unique protonation behavior of the 1,2-diaminoethane (also referred to as ethylenediamine) moiety realizes ac onstruction of at umorous pH-resp...